title: Antitumoral effects of 9-cis retinoic acid in adrenocortical cancer.
abstract: The currently available medical treatment options of adrenocortical cancer (ACC) are limited. In our previous meta-analysis of adrenocortical tumor genomics data, ACC was associated with reduced retinoic acid production and retinoid X receptor-mediated signaling. Our objective has been to study the potential antitumoral effects of 9-cis retinoic acid (9-cisRA) on the ACC cell line NCI-H295R and in a xenograft model. Cell proliferation, hormone secretion, and gene expression have been studied in the NCI-H295R cell line. A complex bioinformatics approach involving pathway and network analysis has been performed. Selected genes have been validated by real-time qRT-PCR. Athymic nude mice xenografted with NCI-H295R have been used in a pilot in vivo xenograft model. 9-cisRA significantly decreased cell viability and steroid hormone secretion in a concentration- and time-dependent manner in the NCI-H295R cell line. Four major molecular pathways have been identified by the analysis of gene expression data. Ten genes have been successfully validated involved in: (1) steroid hormone secretion (HSD3B1, HSD3B2), (2) retinoic acid signaling (ABCA1, ABCG1, HMGCR), (3) cell-cycle damage (GADD45A, CCNE2, UHRF1), and the (4) immune response (MAP2K6, IL1R2). 9-cisRA appears to directly regulate the cell cycle by network analysis. 9-cisRA also reduced tumor growth in the in vivo xenograft model. In conclusion, 9-cisRA might represent a promising new candidate in the treatment of hormone-secreting adrenal tumors and adrenocortical cancer.
authors.affiliation: 2nd Department of Medicine, Faculty of Medicine, Semmelweis University, Szentkirályi Str. 46, Budapest, 1088, Hungary.
authors.forename: Diana Rita
authors.initials: DR
authors.lastname: Szabó
authors.forename: Kornélia
authors.initials: K
authors.lastname: Baghy
authors.forename: Peter M
authors.initials: PM
authors.lastname: Szabó
authors.forename: Adrienn
authors.initials: A
authors.lastname: Zsippai
authors.forename: István
authors.initials: I
authors.lastname: Marczell
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Nagy
authors.forename: Vivien
authors.initials: V
authors.lastname: Varga
authors.forename: Katalin
authors.initials: K
authors.lastname: Éder
authors.forename: Sára
authors.initials: S
authors.lastname: Tóth
authors.forename: Edit I
authors.initials: EI
authors.lastname: Buzás
authors.forename: András
authors.initials: A
authors.lastname: Falus
authors.forename: Ilona
authors.initials: I
authors.lastname: Kovalszky
authors.forename: Attila
authors.initials: A
authors.lastname: Patócs
authors.forename: Károly
authors.initials: K
authors.lastname: Rácz
authors.forename: Peter
authors.initials: P
authors.lastname: Igaz
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy*; D000077556:Alitretinoin; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019295:Computational Biology / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D012739:Gonadal Steroid Hormones; D000077556:Alitretinoin; D014212:Tretinoin